Current and new oral Anti-coagulation. Lancashire and Cumbria Network 2 February 2012

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1 Current and new oral Anti-coagulation Lancashire and Cumbria Network 2 February 2012

2 Question Warfarin is an abbreviation What does the W stand for? What is this plant and what is the connection with warfarin?

3 Warfarin Developed by the Wisconsin Alumni Research Foundation Derivative of dicoumarol which is formed by fungal action on coumarin in sweet clover

4 Efficacy of Warfarin No. of Events Patient- years AFASAK Risk Reduction, % BAATAF CAFA SPAF SPINAF Combined* *Total risk reduction for all 5 studies combined is 68% Warfarin Better Warfarin Worse

5 Patients Assigned to Warfarin in AF Trials Intensity of Anticoagulation When Stroke Occurred INR Ratio AFASAK CAFA SPAF I BAATAF SPINAF PT Ratio (ISI 2.4) INR: Target range for individual study

6 The GRASP-AF tool- dashboard view- CHA 2 DS 2 -VASc

7 CHART Online uploads PCTs 98 Practices 1622 Total list size Patients with AF Patients on oral anti-coagulant 11.7 million 207,388 (1.78%) 114,270 (55.1%) Monday 23 January 2012

8 NICE estimate that of 355,000 patients who should be taking warfarin 189,000 are actually receiving it. An additional 166,000 should be receiving it NICE costing report 2006

9 Extrapolated Population estimates for England (NICE estimates) Prevalence 1.78% (1.28%) Number of AF patients 978,922 (639,000) Number on oral anti-coagulant 538,000 55% (191,500 29%)

10 % Warfarin treatment by Age CHADS>1

11 Contra-indications York study Absolute % Relative % Patient declined 93 12% Doctor s decision % Not coded 43 5% K Griffith A Graham

12 What Award is Colin Firth receiving in this picture?

13 Birmingham Atrial Fibrillation Treatment of the Aged Study Mean age 81.5 years Lancet, 370: 493 (August )

14 BAFTA - primary endpoints Primary endpoints Fatal or non-fatal disabling stroke Other intracranial haemorrhage Arterial embolism Warfarin 1.8 % / year Aspirin 3.8 % / year Relative risk 0.48 (95 % CI )

15 BAFTA Annual risk of extra-cranial haemorrhage Warfarin 1.4 % Aspirin 1.6 % Warfarin did not increase haemorrhagic risk in comparison with aspirin

16 Alternatives to warfarin

17 ACTIVE W Study Risk of stroke in relation to time in therapeutic range NEJM 2008;118:2029

18 ACTIVE W Odds ratio V TTR Log (Odds ratio) = x TTR NEJM 2008;118:2029

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20 RE-LY Study Stroke or Systemic embolism NEJM, Sept 2009

21 RE-LY Study Types of stroke Dab110 Dab150 Warfarin NNT Stroke / Syst embolism Embolic stroke Haemorrhagic stroke Any stroke Disabling or fatal stroke

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23 RELY - Mean time in therapeutic range by country

24 MHRA Advisory dabigatran December 2011 Dabigatran (Pradaxa ): risk of serious haemorrhage need for renal function testing A number of cases of serious and fatal haemorrhage have been reported in elderly patients with renal impairment who were receiving dabigatran. Renal function should be assessed in all patients before starting dabigatran and at least once a year in patients older than 75 years or those with a suspected decline in renal function. Dabigatran is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min)

25 Meta analysis dabigatran and risk of MI / ACS Uchino Arch Int Med 2012:

26 Apixaban stroke / systemic embolism

27 Apixaban AVERROES study

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29 Apixaban AVERROES major bleeding

30 Rivaroxaban -Primary Efficacy Outcome Stroke and non-cns Embolism Cumulative event rate (%) Rivaroxaban Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001

31 Rivaroxaban Primary Efficacy Outcome by Quartiles of cttr Center TTR Rivaroxaban Events % Event Rate Based on Rosendaal method with all INR values included Based on Safety Population Event Rates are per 100 patient-years Events % Warfarin Event Rate % % % % HR (95% CI) 0.71 (0.48, 1.03) 0.83 (0.62, 1.29) 0.92 (0.62, 1.28) 0.77 (0.49, 1.12)

32 Rivaroxaban - Time in Therapeutic Range (TTR) INR range Median (25 th, 75 th ) < ( ) 1.5 to < ( ) 1.8 to < ( ) 2.0 to ( ) >3.0 to ( ) >3.2 to ( ) > ( ) Based on Rosendaal method with all INR values included Based on Safety Population

33 Time in therapeutic range / CHADS TTR CHADS RELY Dabigatran 64 % 2.1 ARISTOTLE Apixaban 62 % 2.1 ROCKET Rivaroxaban 58 % 3.5

34 Drug comparisons Dabigatran Rivaroxaban Apixaban Half life Excretion 85% renal 33% renal 25% renal 67% hepatic 75% non-renal Dose 150mg 20mg 5mg Step Down 110mg 15mg 2.5mg

35 Position of drugs with NICE Dabigatran Appeal against FAD February 7 Rivaroxaban ACD published 9 Jan 2012 Guidance expected May 2012 Apixaban Draft scope 23 Jan 2012 Guidance expected May 2013

36 Conclusions Even though warfarin is an old drug it is very effective The new drugs offer a great opportunity amongst those patients who cannot take warfarin for logistic reasons The jury is out on whether it is appropriate to use the new drugs in patients with good INR control on warfarin